Oral Therapy for the Treatment of Rosacea

Hilary Baldwin, MD
Department of Dermatology, State University of New York, Brooklyn, NY, USA

The Disease

Rosacea is a common condition that is prevalent worldwide. Its
incidence is said to be higher in fair-skinned patients, however it
is also seen in Asians and African-Americans. Rosacea occurs in
both men and women most often after the age of 30 years. It is
characterized by the presence of one or more of the following:

Central facial erythema and telangiectasias

Papules and pustules

Granulomatous nodules

Phyma formation

Ocular changes

Known triggers include UV exposure alcohol intake, spicy foods,
and changes in temperature. However, sometimes flares and
remissions occur with no rationale.

Classification

A National Rosacea Society1 committee has classified rosacea
into four types based on predominant lesion morphology:

Erythematotelangiectatic

Flushing and persistent central facial erythema with telangiectasias. Central facial edema, stinging and burning of the skin, as well as dryness occurs.

Most difficult subtype to treat

Topical and oral therapy largely ineffective

Laser and light therapy most effective

Papulopustular

Papules and pustules often seen with persistent facial erythema.

Easiest subtype to treat

May respond to topical therapy

Oral agents more effective. May be used as first-line therapy, when topicals are ineffective or when it is important to speed up the response time.

This system allows therapy evaluation based on similar lesion
types; there are few medications or therapies that are significantly
effective in more than one category.2

Pathophysiology

Inflammation plays an important role in lesion formation,
however the etiology of rosacea is not well understood. It is
generally believed that there is no microorganism involved in
the pathogenesis of rosacea.

Common denominators are believed to include inflammation and
degradation of the dermal connective tissue; angiogenesis caused
by the upregulation of proinflammatory cytokines; neutrophil
chemotaxis; and the production of nitric oxide, reactive oxygen
species, and matrix metalloproteinases.

In the face of an absence of a defined pathogenesis, treatment
has traditionally been based on disease endpoints rather than
targeting the underlying problems.:

Inflammation is treated with anti-inflammatory agents.

Flushing is treated with vasoconstrictors.

Telangiectasias are treated with vascular lasers.

Pustules are treated with antibiotics without a target organism.

Vasoconstricting Agents

A number of agents have been reported anecdotally to reduce
flushing including beta blockers in low doses,3 naloxone,4
ondansetron,5 aspirin,6 and serotonin reuptake inhibitors.7
Clonidine, at 0.05mg b.i.d., has also been reported to be effective
for reducing flushing.8 While this suboptimal dose does not
reduce blood pressure, it does lower baseline malar temperature
by peripheral vasoconstriction.

Antibiotics

Oral antibiotics have been used off-label since the 1950s, but
until May of 2006 none had been approved for treating this
condition. Antibiotics are highly effective in papulopustular
rosacea. However, justification for their use must be based on the
recognition that there is little or no evidence demonstrating that
rosacea is the result of a bacterial infection, and that reports of
antibiotic resistance have been increasing over the past 10 years.

Tetracyclines

Because tetracyclines act to reduce inflammation, they are very
effective for papulopustular acne and rosacea with substantial
improvement seen after 3–4 weeks. However, relapses often
occur after discontinuation.9 Tetracycline 250–1000mg q.d.,
doxycycline 100–200mg q.d., and minocycline 100–200mg q.d.
are most commonly used. Using oral tetracyclines until clinical
improvement is seen, then tapering to topical antibiotics, offers
a way to maintain control and minimize relapses. However, we
should not ignore the lessons learned from the use of long-term
oral antibiotics and the resultant potential for bacterial resistance
that have developed while treating other skin diseases.

Anti-inflammatory Dose Doxycycline –
A New Treatment Option

The reason why tetracyclines are so effective for treating rosacea
is likely due to their anti-inflammatory properties, not their role
as antibiotics. In May 2006, the FDA approved the first oral
prescription therapy for the treatment of inflammatory lesions
(papules and pustules) of rosacea in adult patients. This product,
doxycycline (Oracea™), is a once daily 40mg capsule containing
30mg immediate-release and 10mg delayed-release beads. It
allows for blood levels of doxycycline to stay within a narrow
window: high enough to act as an anti-inflammatory medication,
but well beneath the antimicrobial threshold. In two Phase III,
double-blind, placebo-controlled clinical trials, patients receiving
this drug experienced a 61% and 46% mean reduction in
inflammatory lesions compared with 29% and 20%, respectively
for placebo (p < 0.001 for each study).10 Side-effects were similar
to placebo. Most notably, since the low dose exerts no selection
pressure on bacteria, there were no yeast infections reported and
continued use did not result in antibacterial resistance.

Erythromycin

Erythromycin is effective for treating papulopustular rosacea, but
patients often complain of GI side-effects. Second generation
macrolides have been shown to be more effective than
erythromycin. However, resistance has been noted in patients in
whom an infectious etiology cannot be demonstrated.

Metronidazole

Oral metronidazole, 200mg b.i.d., is often used for long-term
treatment of rosacea in Europe.11,12 In a double-blind study, this
drug was shown to be as effective as oxytetracycline 250mg.
b.i.d.12 Side-effects include rare neuropathy and seizures. Alcohol
abstinence is required during use.2

Isotretinoin

Isotretinoin is less commonly used for the treatment of rosacea
than it is for acne vulgaris. By reducing the size and number of
sebaceous glands, treatment-resistant rosacea patients who were
given this drug had fewer papules and pustules, a decrease in
erythema, and a reduction in nasal volume in rhinophyma.13,14
Unlike acne therapy where isotretinoin is generally curative,
improvement in rosacea is often not as long-lasting. Erdogan, et
al. used a low dose of 10mg daily for 4 months with a significant
reduction in inflammatory lesions, erythema and telangiectasia
at 9 weeks.15 Long-term, low-dose therapy is highly effective
in controlling papulopustular rosacea. Use of isotretinoin in
adult females of child-bearing potential requires birth control
monitoring and extensive counseling because of its teratogenic
properties. Distribution of isotretinoin is restricted by a special
computer-based risk management program approved by the
FDA, designed to further the public health goal to eliminate
fetal exposure to isotretinoin. For more information see
www.ipledgeprogram.com

Conclusion

Novel uses of old medications and new formulations of systemic
medications have broadened the therapeutic armamentarium
for treating rosacea patients. It is of primary importance to
offer patients safe and effective therapies for this chronic and
incurable condition, improving both the clinical and psychosocial
consequences of rosacea.

Editor's Commentary

As Dr. Baldwin points out, there is increasing concern in the
medical community about prolonged ingestion of oral antibiotics
due to bacterial resistance patterns. This concern has been further
validated by the recent elucidation of the complete genome of
P. acnes and the finding that this organism possesses inherent
mechanisms enabling it to transfer a variety of resistance genes
to other microbial species.1,2 Thus, while oral antibiotics have
long been the mainstay of rosacea therapy, apprehension about
microbiological consequences has tempered enthusiasm for this
type of treatment. Complete alcohol avoidance required of those
receiving oral metronidazole, and the myriad of potential adverse
events associated with isotretinoin have likewise made these
alternate agents difficult to administer.

Prior investigation of very low-dose doxycycline suggested
efficacy for rosacea.3 Thus, the recent FDA approval and
commercial release of a subantimicrobial and purely antiinflammatory
dose of this drug in a convenient once-daily
formulation might, indeed, have several advantages, i.e. no
development of resistance and fewer or no problems with yeast
infections. However, comparative clinical trials to demonstrate
such advantages have not been done. The goal of such therapy
is to administer an antibiotic moiety in a dosage formulation
that preserves anti-inflammatory properties but eliminates antiinfective
properties, thereby avoiding ecologic pressure on
bacteria to become resistant. The exact mechanism(s) by which
anti-inflammatory doxycycline improves rosacea is uncertain.
Suppression of cytokine and chemokine elaboration, inhibition
of matrix metalloproteinases, decreased vasodilatation and other
properties have been described.4 This formulation is also notable
for its lack of photosensitivity, and for the minimal risk of
secondary candidiasis and troublesome side-effects traditionally
associated with the tetracycline family.

Another promising oral therapy for rosacea involves the use of an
oral blend of nicotinamide and zinc (Nic/Zn).5 The formulation
tested contained nicotinamide 750mg and zinc 25mg as active
ingredients, along with small amounts of copper and folic acid.
Nearly 80% of subjects reported a patient global evaluation of
“moderately” or “much” better when compared with baseline
after 8 weeks. Similar to anti-inflammatory dose doxycycline,
the precise mechanism of action is uncertain, but suppression of
vascular permeability, reduced accumulation of inflammatory
cells, depressed mast cell degranulation, and stabilization of
lysosomes have all been implicated.6 If larger scale and longer
duration studies verify the aforementioned data, then Nic/Zn may
further expand our oral therapeutic options.

Rosacea patients often exhibit “irritable” skin, which may be
hyper-reactive to a host of topical medications as well as to overthe-
counter skin care products.7 Oral therapy may be mandatory
for such individuals, and transitioning to topical maintenance
should be deferred until significant improvement occurs.